scholarly journals The Expanding Role of Alternative Splicing in Vascular Smooth Muscle Cell Plasticity

2021 ◽  
Vol 22 (19) ◽  
pp. 10213
Author(s):  
Immanuel D. Green ◽  
Renjing Liu ◽  
Justin J. L. Wong
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Alternative Splicing ◽  
Vascular Smooth Muscle ◽  
Gene Expression Regulation ◽  
Environmental Cues ◽  
Cell Plasticity ◽  
Rna Biology ◽  
Gene Expression Levels

Vascular smooth muscle cells (VSMCs) display extraordinary phenotypic plasticity. This allows them to differentiate or dedifferentiate, depending on environmental cues. The ability to ‘switch’ between a quiescent contractile phenotype to a highly proliferative synthetic state renders VSMCs as primary mediators of vascular repair and remodelling. When their plasticity is pathological, it can lead to cardiovascular diseases such as atherosclerosis and restenosis. Coinciding with significant technological and conceptual innovations in RNA biology, there has been a growing focus on the role of alternative splicing in VSMC gene expression regulation. Herein, we review how alternative splicing and its regulatory factors are involved in generating protein diversity and altering gene expression levels in VSMC plasticity. Moreover, we explore how recent advancements in the development of splicing-modulating therapies may be applied to VSMC-related pathologies.

scholarly journals Effect of PGC-1αon Proliferation, Migration, and Transdifferentiation of Rat Vascular Smooth Muscle Cells Induced by High Glucose

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Xiaoqiang Qi ◽  
Yujing Zhang ◽  
Jing Li ◽  
Dongxia Hou ◽  
Yang Xiang
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
High Glucose ◽  
Muscle Cells ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene

We assessed the role of PGC-1α (PPARγ coactivator-1 alpha) in glucose-induced proliferation, migration, and inflammatory gene expression of vascular smooth muscle cells (VSMCs). We carried out phagocytosis studies to assess the role of PGC-1α in transdifferentiation of VSMCs by flow cytometry. We found that high glucose stimulated proliferation, migration and inflammatory gene expression of VSMCs, but overexpression of PGC-1α attenuated the effects of glucose. In addition, overexpression of PGC-1α decreased mRNA and protein level of VSMCs-related genes, and induced macrophage-related gene expression, as well as phagocytosis of VSMCs. Therefore, PGC-1α inhibited glucose-induced proliferation, migration and inflammatory gene expression of VSMCs, which are key features in the pathology of atherosclerosis. More importantly, PGC-1α transdifferentiated VSMCs to a macrophage-like state. Such transdifferentiation possibly increased the portion of VSMCs-derived foam cells in the plaque and favored plaque stability.

scholarly journals Cilostazol inhibits uremic toxin–induced vascular smooth muscle cell dysfunction: role of Axl signaling

2017 ◽  
Vol 312 (3) ◽  
pp. F398-F406 ◽  
Author(s):  
Chien-Hsing Lee ◽  
Yi-Jen Hung ◽  
Yi-Shing Shieh ◽  
Chu-Yen Chien ◽  
Yu-Juei Hsu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cell ◽  
Muscle Cell ◽  
Vascular Smooth Muscle Cell ◽  
Uremic Toxin ◽  
Cell Functions

Chronic kidney disease (CKD) is associated with increased cardiovascular mortality, and vascular smooth muscle cell (VSMC) dysfunction plays a pivotal role in uremic atherosclerosis. Axl signaling is involved in vascular injury and is highly expressed in VSMCs. Recent reports have shown that cilostazol, a phosphodiesterase type 3 inhibitor (PDE3), can regulate various stages of the atherosclerotic process. However, the role of cilostazol in uremic vasculopathy remains unclear. This study aimed to identify the effect of cilostazol in VSMCs in the experimental CKD and to investigate whether the regulatory mechanism occurs through Axl signaling. We investigated the effect of P-cresol and cilostazol on Axl signaling in A7r5 rat VSMCs and the rat and human CKD models. From the in vivo CKD rats and patients, aortic tissue exhibited significantly decreased Axl expression after cilostazol treatment. P-cresol increased Axl, proliferating of cell nuclear antigen (PCNA), focal adhesion kinase (FAK), and matrix metalloproteinase-2 (MMP-2) expressions, decreased caspase-3 expression, and was accompanied by increased cell viability and migration. Cilostazol significantly reversed P-cresol-induced Axl, downstream gene expressions, and cell functions. Along with the increased Axl expression, P-cresol activated PLCγ, Akt, and ERK phosphorylation and cilostazol significantly suppressed the effect of P-cresol. Axl knockdown significantly reversed the expressions of P-cresol-induced Axl-related gene expression and cell functions. Cilostazol with Axl knockdown have additive changes in downstream gene expression and cell functions in P-cresol culture. Both in vitro and in vivo experimental CKD models elucidate a new signal transduction of cilostazol-mediated protection against uremic toxin-related VSMCs dysfunction and highlight the involvement of the Axl signaling and downstream pathways.

Abstract 580: Regulation of Inflammatory Gene Expression by Angiotensin II-induced KLF4 in Vascular Smooth Muscle Cells

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Wen Jin ◽  
Marpadga A Reddy ◽  
Zhuo Chen ◽  
Sadhan Das ◽  
Linda Lanting ◽  
...  
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Transcription Factors ◽  
Angiotensin Ii ◽  
Vascular Smooth Muscle ◽  
Phenotypic Switching ◽  
Ang Ii ◽  
Inflammatory Genes ◽  
Anti Inflammatory

Angiotensin II (Ang II)-mediated vascular smooth muscle cell (VSMC) dysfunction plays a critical role in the pathogenesis of Cardiovascular Diseases (CVDs). However, the role of Ang II-induced transcription factors in the diverse effects of Ang II remains unclear. We profiled Ang II induced gene expression by microarray analysis of RNA isolated from Ang II-treated and control VSMC. Our results identified numerous differentially regulated genes including several key transcription factors in Ang II-stimulated VSMC compared with controls. Ingenuity Pathway Analysis indicated that Ang II-regulated genes are involved in VSMC dysfunction highly relevant to CVDs. We validated the expression of several genes by RT-qPCR and further characterized the functions of the most differentially regulated gene, KLF4, known to regulate growth factor induced VSMC phenotypic switching. We demonstrated that Ang II induced the expression of KLF4 in cultured VSMC in vitro , in mice aortas cultured ex vivo , and in aortas isolated from Ang II-infused mice in vivo . Ang II-induced KLF4 expression was inhibited by Losartan, demonstrating regulation via the AT1 receptor. Transfection experiments using WT and mutant KLF4 promoter constructs revealed the key role of cis -elements with consensus binding sites for p53, SP1 and YY1 in Ang II-induced KLF4 promoter activation. Next, we performed gene expression profiling by Affymetrix gene arrays after siRNA mediated KLF4 knockdown in VSMC. The differentially expressed genes were subsequently analyzed by DAVID to obtain enriched biological processes and potential pathways relevant to cardiovascular functions. Results showed that KLF4 knockdown upregulated the expression of several genes related to cell proliferation and hypertrophy. Interestingly, KLF4 knockdown also enhanced the expression of multiple pro-inflammatory genes including IL-6 and downregulated several anti-inflammatory genes including Thrombomodulin, suggesting an anti-inflammatory role for KLF4 in VSMC. Together, these results suggest that KLF4 may act as a novel molecular brake to modulate Ang II actions that, when disrupted, can further augment Ang II mediated VSMC dysfunction associated with vascular diseases.

scholarly journals Involvement of DHX9/YB-1 complex induced alternative splicing of Krüppel-like factor 5 mRNA in phenotypic transformation of vascular smooth muscle cells

2019 ◽  
Vol 317 (2) ◽  
pp. C262-C269
Author(s):  
Wei Huan ◽  
Jing Zhang ◽  
Yingke Li ◽  
Kangkang Zhi
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Alternative Splicing ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Smooth Muscle Cell ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cell ◽  
Muscle Cells ◽  
Phenotypic Transformation

Phenotypic transformation of vascular smooth muscle cells is a key phenomenon in the development of aortic dissection disease. However, the molecular mechanisms underlying this phenomenon have not been fully understood. We used β-BAPN combined with ANG II treatment to establish a disease model of acute aortic dissection (AAD) in mice. We first examined the gene expression profile of aortic tissue in mice with AAD using a gene chip, followed by confirmation of DExH-box helicase 9 (DHX9) expression using RT-PCR, Western blot, and immunofluorescence analysis. We further developed vascular smooth muscle cell-specific DHX9 conditional knockout mice and conducted differential and functional analysis of gene expression and alternative splicing in mouse vascular smooth muscle cells. Finally, we examined the involvement of DHX9 in Krüppel-like factor 5 ( KLF5) mRNA alternative splicing. Our study reported a significant decrease in the expression of DHX9 in the vascular smooth muscle cells (VSMCs) of mice with AAD. The smooth muscle cell-specific knockout of DHX9 exacerbated the development of AAD and altered the transcriptional level expression of many smooth muscle cell phenotype-related genes. Finally, we reported that DHX9 may induce alternative splicing of KLF5 mRNA by bridging YB-1. These results together suggested a new pathogenic mechanism underlying the development of AAD, and future research of this mechanism may help identify effective therapeutic intervention for AAD.

scholarly journals The Increase of pFAK and THBS1 Protein and Gene Expression Levels in Vascular Smooth Muscle Cells by Histamine-treated M1 Macrophages

2019 ◽  
Author(s):  
Mohsen Khosravi ◽  
Mohammad Najafi ◽  
Abdollah Amirfarhangi ◽  
Mahdi Karimi ◽  
Fahimeh Fattahi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
M1 Macrophages ◽  
Expression Levels ◽  
Protein Levels ◽  
Gene Expression Levels

Atherosclerosis is developed due to the formation of atheroma plaques in the coronary arteries. In this process, M1 macrophages and vascular smooth muscle cells (VSMCs) are the main functional cells. Inflammatory mediators such as histamine may inflame M1 macrophages. The aim of this study was to determine the effect of M1 macrophage secretion contents on the gene and protein expression levels of focal adhesion kinase (FAK), vasodilator-stimulated phosphoprotein (VASP), and thrombospondin1 (THBS1). Whole blood samples from the six healthy subjects (stenosis<5%), and six patients (stenosis>70%) were prepared and peripheral blood mononuclear cells (PBMCs) were isolated. Then monocytes were differentiated into M1 macrophages using 100 ng/mL granulocyte-macrophage colony stimulating factor (GM-CSF). The differentiated M1 macrophages were treated with histamine (10-6 M), and their secretion contents were harvested and added to the culture medium of VSMCs. The FAK, VASP, and THBS1 gene expression and protein levels were measured using RT-qPCR and western blot techniques in VSMCs, respectively. The FAK and THBS1 gene expression levels significantly increased in VSMCs after adding secretion contents obtained from histamine-treated M1 macrophages (p=0.023 and 0.05, respectively), while significant results were not observed for VASP gene (p=0.45). In converse with the phosphorylated VASP (pVASP) (p<0.34), the phosphorylated FAK (pFAK) and THBS1 protein levels increased in VSMCs (p<0.001). We concluded that in inflammatory conditions, the immune events could affect the macrophages by histamine. The activated macrophages could locally activate signaling  pathways via FAK and THBS1 genes that are effective in the proliferation and migration of VSMCs.

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